Sun_2025_Bioorg.Chem_163_108747

This study introduces a Fragment-Informed Structure-Activity Relationship (FI-SAR) paradigm for developing cholinesterase inhibitors through strategic coupling of amino-functionalized fragments with quinoline scaffolds. A library of 105 conjugates was synthesized and comprehensively assessed to delineate fragment-to-conjugate activity transfer. Quantitative analysis revealed a positive correlation between fragment potency and conjugate inhibitory activity, with phenolic Mannich base derivatives showing the strongest interdependence. Notably, representative conjugate L4R1-3 achieved sub-nanomolar AChE inhibition (IC50 = 4.6 nM), outperforming clinical references such as donepezil. Furthermore, dual-target inhibitors were constructed (e.g., L1-3, AChE/BChE IC50 = 8.1/0.58 microM) by using FI-SAR strategy. Molecular simulations confirmed stable binding modes of high-activity conjugates within the AChE/BChE active site. This work establishes a streamlined FI-SAR framework, emphasizing that strategic fusion of privileged pharmacophores (e.g., phenolic Mannich bases) with versatile scaffolds like quinoline can accelerate multi-target drug discovery, suggesting broader applicability to enzyme-driven diseases.